We have used molecular genetics to identify and characterize the C-fiber low threshold mechanoreceptor (C- LTMR), a DRG sensory neuron proposed to contribute to injury-induced touch hypersensitivity and the affective, or emotional, component of touch. We propose to assess the in vivo functions of C-LTMRs in adult mice, their morphologies, and their postsynaptic targets in the dorsal horn in an attempt to elucidate key mechanosensitive and nociceptive circuits. We propose to characterize the anatomical features of this poorly understood neuronal population at single cell resolution using newly developed mouse molecular-genetic tools. To further define a C-LTMR circuit we will couple these tools with physiological approaches to test the hypothesis that PKC3+ interneurons of dorsal horn lamina IIiv are post-synaptic partners of C-LTMRs. Finally, we will generate new mouse lines to ablate C-LTMRs in the adult to directly test whether C-LTMRs are key mediators of mechanical allodynia and hairy skin soft touch. Together, this research will reveal the morphological properties of C-LTMRs, define a C-LTMR-specific neural circuit, and establish the role for C- LTMRs in mechanosensation and allodynia. PUBLIC HEALTH RELEVANCE: Proper identification and functional characterization of sensory neuronal populations is central not only to our understating of how normal touch sensations arise, but also how sensory pathways converge in diseases such as injury induced mechanical hypersensitivity. Our goal is to identify and characterize a circuit mediating touch sensation and possibly mechanical allodynia by genetically targeting pre- and post-synaptic sensory neurons of the dorsal horn and elucidating their anatomical, physiological and behavioral properties.